Document Detail


Small-molecule inhibitors of signal transducer and activator of transcription 3 protect against angiotensin II-induced vascular dysfunction and hypertension.
MedLine Citation:
PMID:  23266544     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Angiotensin II (Ang II) is known to promote vascular disease and hypertension in part by formation of cytokines, such as interleukin-6. However, the role of signal transducer and activator of transcription 3 (STAT3) in these processes and Ang II/interleukin-6 signaling is unclear. Using 2 models, we tested the hypothesis that STAT3 is essential for Ang II-induced vascular dysfunction and hypertension. Incubation of isolated carotid arteries from C57BL/6J mice with Ang II overnight increased superoxide ≈2-fold and reduced vasodilator responses to the endothelium-dependent agonist acetylcholine by ≈50% versus controls (P<0.05). These effects were prevented by the addition of small-molecular inhibitors of STAT3 activation (S3I-201 or STATTIC). In vivo, administration of Ang II (1.4 mg kg(-1) day(-1)) using osmotic minipumps increased arterial pressure by ≈40 mm Hg at day 14 compared with vehicle-treated mice, and this effect was prevented by S3I-201 treatment (5 mg/kg IP, QOD). After systemic treatment with Ang II, dilator responses to acetylcholine were reduced by ≈30% to 50% in carotid artery and basilar arteries, whereas S3I-201 treatment prevented most of this impairment (P<0.05). In contrast to effects on vascular function and blood pressure, S31-201 did not prevent Ang II-induced hypertrophy in the carotid artery. These findings provide the first evidence that inhibitors of STAT3 activation protect against Ang II-induced oxidative stress, endothelial dysfunction, and hypertension. Because Ang II promotes vascular disease in the presence of multiple cardiovascular risk factors, these results suggest that selective targeting of STAT3 may have substantial therapeutic potential.
Authors:
Andrew W Johnson; Dale A Kinzenbaw; Mary L Modrick; Frank M Faraci
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-12-24
Journal Detail:
Title:  Hypertension     Volume:  61     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-17     Completed Date:  2013-03-20     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  437-42     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / pharmacology
Aminosalicylic Acids / pharmacology
Angiotensin II / toxicity*
Animals
Antihypertensive Agents / pharmacology
Aorta / drug effects,  metabolism,  physiopathology
Benzenesulfonates / pharmacology
Carotid Arteries / drug effects,  metabolism,  physiopathology
Cyclic S-Oxides / pharmacology
Endothelium, Vascular / drug effects*,  metabolism,  physiopathology
Hypertension / chemically induced,  metabolism,  physiopathology,  prevention & control*
Male
Mice
Nitroprusside / pharmacology
Oxidative Stress / drug effects,  physiology*
Phosphorylation / drug effects
STAT3 Transcription Factor / antagonists & inhibitors*,  metabolism
Superoxides / metabolism
Vasoconstrictor Agents / pharmacology
Vasodilator Agents / pharmacology
Grant Support
ID/Acronym/Agency:
HL-113863/HL/NHLBI NIH HHS; HL-38901/HL/NHLBI NIH HHS; HL-62984/HL/NHLBI NIH HHS; NS-24621/NS/NINDS NIH HHS; P01 HL062984/HL/NHLBI NIH HHS; R01 HL038901/HL/NHLBI NIH HHS; R01 HL113863/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Aminosalicylic Acids; 0/Antihypertensive Agents; 0/Benzenesulfonates; 0/Cyclic S-Oxides; 0/NSC 74859; 0/STAT3 Transcription Factor; 0/Vasoconstrictor Agents; 0/Vasodilator Agents; 0/stattic; 11062-77-4/Superoxides; 11128-99-7/Angiotensin II; 169D1260KM/Nitroprusside; 76898-47-0/15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
Comments/Corrections

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